Apixaban is an active pharmaceutical ingredient used as anticoagulant for the treatment of venous thromboembolic events.
Apixaban has chemical name, 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[5,4-c]pyridine-3-carboxamide and has the following chemical formula (I):

Some solvates of Apixaban are known, for example, are known the solvates of Apixaban with formamide or with dimethylformamide, both having stoichiometry 1:1.
Apixaban dihydrate, i.e. the hydrate form of Apixaban having two molecules of water per one of Apixaban is also known.
In literature are disclosed some routes of synthesis of Apixaban, in particular, in WO2007/0001385 is described in detail the first industrial synthesis of Apixaban on multi-Kilos scale.
The PCT application WO2007/0001385 discloses in example 6 a process for the preparation of Apixaban by amidation reaction on 10 Kg scale of the Apixaban ethyl ester according to the following reaction scheme:

According said procedure, using anhydrous ammonia in propylene glycol and performing the reaction for at least 12 hours at 90° C., Apixaban was obtained with 94.6% of isolated molar yield.
The biggest advantage of the method disclosed in example 6, also in comparison with examples 7 and 9 of WO2007/0001385, is that such a method provides Apixaban having the polymorphic form named N−1, a solid form which is well characterized in example 9 of the same application and which is the thermodynamically stable form of Apixaban.
According to the regulatory information provided by the originator, Apixaban form N−1 is the form currently on the market, so that, with the aim of providing an active pharmaceutical ingredients which provides exactly the same physical-chemical and therapeutical properties of that the originator for the generic market, it is important to find a method for the preparation of Apixaban which provides the polymorphic form N−1.
In the publication J. Med. Chem., 2007, vol. 50, 22, pag. 5339-5356, Apixaban is prepared from Apixaban ethyl ester with aqueous ammonia at 5% in ethylene glycol heating to 120° C. for 4 hours with a molar yield of 76%, according to the following reaction scheme:

Unfortunately, nothing is said relating to the solid form of Apixaban thus prepared.
The publication Synthetic Communication, 43, pag. 72-79, (2013) discloses a method for the preparation of Apixaban from the intermediate Apixaban ethyl ester using 25% aqueous ammonia in methanol at 65° C. for 5 hours with 91% molar yield.
Nevertheless such a method, probably because is carried out in Methanol instead of in a glycol solvent, does not provide Apixaban form N−1, indeed the m.p. of the product is 171-173° C. which is different from that of the form N−1 being 235-237° C. Moreover no data relating to the purity of the product are provided.
In the patent publication WO2013/119328, example 2, the synthesis of Apixaban was carried out from Apixaban ethyl ester using 5% aqueous ammonia in propylene glycol at 100° C. overnight. The reaction mixture was not seeded with the form N−1 so that at the end of the work-up a different solid form, named Form I, has been isolated. Apixaban Form I thus prepared is Apixaban 1,2-propylen glycol hemisolvate.
Considering the above prior art, and our preliminary experimental results, the presence of a glycol solvent, such as in example 6 of WO2007/0001385, seems to promote the preparation of the polymorphic form N−1, while it appears that the presence of an alcohol solvent as in example 7 and 9 WO2007/0001385 tends to provide the solid form H2-2.
Therefore, to prepare Apixaban form N−1 it appears convenient to isolate Apixaban from a glycol solvent.
Nevertheless, although the industrial method for the preparation of Apixaban form N−1 disclosed in WO2007/0001385 already uses a glycol solvent, such a method has the drawback that it requires long reaction times at high temperature, i.e. at least 12 hours at 90° C. or, according to WO2013/119328, 100° C. overnight, or 4 hours at 120° C. (see above J. Med. Chem. (2007)).